Contemporary Reviews in Cardiovascular Medicine

Recent Update to the US Cholesterol Treatment Guidelines

AbstractThe 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guideline advocated several changes from the previous Adult Treatment Panel III guidelines. Assuming full implementation, the 2013 ACC/AHA guideline would identify 13 million Americans as newly eligible for consideration of statin therapy. Three features of the 2013 ACC/AHA guideline primarily responsible for these differences are the specific risk assessment tool endorsed, the risk threshold considered sufficient to warrant primary prevention statin therapy, and the decision not to include cholesterol treatment targets. There is no consensus among international guidelines on the optimal approach to these 3 components. The 2013 ACC/AHA guideline recommends assessing absolute risk with the Pooled Cohort equations, which were developed to improve on previous risk assessment models by including stroke as an outcome and by broadening racial and geographic diversity. Each of the leading international guidelines recommends a different equation for absolute risk assessment. The 2013Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

ACC/AHA guideline advises consideration of statin therapy for an estimated 10-year risk of atherosclerotic vascular disease of 7.5%, which is lower than the thresholds recommended by other leading international guidelines. Lastly, the 2013 ACC/ AHA guideline does not endorse a treat-to-target strategy but instead specifies the appropriate intensity of statin for each risk category. This approach is shared by the National Institute for Health and Care Excellence guidelines but differs from other international guidelines. In this review, we summarize the 2013 ACC/AHA cholesterol guideline recommendations and compare them with recommendations from Adult Treatment Panel III and other leading international guidelines. (Circulation. 2016;133:1795-1806. DOI: 10.1161/CIRCULATIONAHA.116.021407.) Key Words:cardiovascular diseases cholesterol guideline [publication type] prevention and control

D espite reductions in the mortality rate for cardiovascular

disease (CVD) among high- and middle-income countries during the past 2 decades, approximately one third of global 60-year-old nonsmoking white man without established CVD or diabetes mellitus with no family history of premature CVD who currently takes no medications. He is 69 in (175 cm) tall deaths are still attributable to ischemic heart disease and stroke.1 and weighs 180 lb (81.6 kg); his body mass index is 26.6 kg/ These conditions also account for a large proportion of disabil- m2; his blood pressure is 144/86 mmHg; and his fasting lipid ity and global healthcare costs.2,3 Elevated blood cholesterol is profile reveals a total serum cholesterol of 195 mg/dL, low- among the most prevalent modifiable cardiovascular risk factors, density lipoprotein (LDL) cholesterol (LDL-C) of 125 mg/ with medical therapies proven to reduce both CVD incidence dL, high-density lipoprotein cholesterol (HDL-C) of 50 mg/ and related mortality.410 Therefore, clinical practice guidelines dL, and triglycerides of 100 mg/dL (to convert from mg/dL to addressing the treatment of blood cholesterol have a tremen- mmol/L, multiply LDL-C or HDL-C by 0.0259 and multiply dous potential impact on population health and related health- triglycerides by 0.0113). care costs. The most recent US guidelines on the treatment of blood cholesterol11 contain important changes from the previ- 2013 American College of Cardiology/ ous version.12,13 In this review, we aim to summarize the rec- American Heart Association Guideline ommendations from the most recent US cholesterol guideline, highlighting specific changes from the previous version, and in Methodology parallel compare it with other leading international guidelines. The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults11 Guidelines for the Treatment of Blood Cholesterol (2013 ACC/AHA guideline) was commissioned to reflect new Clinical Vignette evidence since the previous Adult Treatment Panel III (ATP To demonstrate differences between the various guidelines, III) guidelines were last updated in 2004.12,13 Whereas previ- we refer to a representative patient (Figure): Consider a ous cholesterol guidelines targeted the prevention of coronary

heart disease (CHD), the 2013 ACC/AHA guideline expanded Cohort equations were derived with data from 4 National the focus to atherosclerotic CVD (ASCVD), including CHD, Heart, Lung, and Blood Institutesponsored cohort studies stroke, and peripheral arterial disease. The 2013 ACC/AHA the Atherosclerosis Risk in Communities (ARIC) study, the task force used a new approach to assess available evidence, Cardiovascular Health Study (CHS), the Coronary Artery focusing on randomized, controlled trials and systematic Risk Development in Young Adults (CARDIA) study, and the reviews and meta-analyses of randomized, controlled trials. Framingham Heart Study (FHS; including original and off- Furthermore, the new guideline differed from the previous spring cohorts)with adjudicated clinical outcomes, includ- iterations in its intended scope. Whereas the ATP III guide- ing myocardial infarction, CHD death, and fatal or nonfatal lines included a comprehensive topical review and recommen- stroke.14 The risk factors meeting the criteria for inclusion in dations for laboratory evaluation, clinical diagnosis, lifestyle the multivariable model were age, sex, total cholesterol, HDL- interventions, and drug therapy, the 2013 ACC/AHA guide- C, systolic blood pressure, antihypertensive treatment status, line focused on answering 3 critical questions: (1) What is diabetes mellitus, and current smoking status. Of these vari- the evidence for LDL-C and nonHDL-C goals in secondary ables, only diabetes mellitus was not included in the modified prevention of ASCVD? (2) What is the evidence for LDL-C FRS endorsed by the ATP III guidelines. Different multivari- and nonHDL-C goals in primary prevention of ASCVD? able models were constructed for white and black individuals, (3) What are the effectiveness and safety of lipid-modifying and caution was recommended when these equations were drugs in the primary and secondary prevention of ASCVD?11 applied to other races and to adults outside the age range of An independent contractor selected the relevant studies to be 40 to 79 years. reviewed for each critical question according to prespecified criteria. This methodology was designed to reduce bias and to Treatment Recommendations ensure that lower-quality studies were not considered when The 2013 ACC/AHA guideline recommended treatment with the recommendations were formulated. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) for 4 categories of individuals: (1) secondary pre- Risk Assessment Model vention for those with established ASCVD, (2) primary pre- A new tool for global risk assessment was introduced with vention of ASCVD for those with LDL-C 190 mg/dL, (3) the 2013 ACC/AHA guideline.11 The previous guidelines rec- primary prevention of ASCVD for individuals with diabetes ommended using a modified Framingham Risk Score (FRS) mellitus and LDL-C of 70 to 189 mg/dL, and (4) primary pre- to estimate the 10-year risk of myocardial infarction or CHD vention of ASCVD for those without diabetes mellitus, with death. Criticisms of this model included the absence of stroke LDL of 70 to 189 mg/dL, but with an estimated 10-year abso- as an outcome and a lack of racial, ethnic, and geographic lute risk of 7.5% as assessed by the Pooled Cohort equa- diversity in the derivation population. In response, the Pooled tions. For this fourth group especially, the guideline authors Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1797

emphasized the importance of shared decision making based would be considered at intermediate risk on the basis of an on a detailed risk discussion between patient and clinician estimated 10-year absolute risk of CHD of 10%. Hence, his before the initiation of statin therapy.15 This clinician-patient LDL-C target would be <130 mg/dL, and given his current discussion should include an assessment of the potential ben- LDL-C of 125 mg/dL, he would not receive statin therapy. efit, possible adverse effects and drug-drug interactions, life- Notably, a white man was used for our representative clini- style changes, management of other risk factors, and of course cal vignette. The difference in estimated risk between the Pooled patient preferences. Additionally, other factors that might Cohort equations and the FRS would be more pronounced if affect net risk reclassification could be used to further inform a black woman, for example, had the same risk factor profile. the treatment decision; these include LDL-C 160 mg/dL or With the Pooled Cohort equations, she would have an estimated evidence of genetic dyslipidemia, elevated lifetime risk, fam- 10-year ASCVD risk of 7.4%, which is considerably higher than ily history of premature CVD, blood levels of high-sensitivity the 2% 10-year CHD risk estimated by the FRS. C-reactive protein 2.0 mg/L, ankle-brachial index <0.9, or abnormal coronary artery calcium score (300 Agatston units 2011 European Society of Cardiology/ or 75th percentile for age, sex, and ethnicity). Individuals at European Atherosclerosis Society Guidelines intermediate risk (10-year absolute risk of 5%7.4%) or low risk (10-year absolute risk <5%) could also be considered for Methodology statin therapy on the basis of patient preferences or perceived The European Society of Cardiology/European Atherosclerosis benefit based on additional factors such as those listed above. Society Guidelines for the Management of Dyslipidaemias16Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

Instead of setting specific LDL-C targets, the 2013 ACC/ (2011 ESC/EAS guidelines) are a comprehensive document AHA guideline essentially suggested a fixed dose (or inten- addressing cardiovascular risk assessment, laboratory evalua- sity) of statin for each risk category, with intended LDL-C tion, lifestyle modifications, drug treatment, and the approach reductions of 30% to 49% and 50% for moderate- and high- to specific clinical settings such as familial dyslipidemias. The intensity statins, respectively. The authors also suggested that ESC/EAS task force based its findings on a comprehensive nonstatin medications could be considered for those at high review of the literature in which greater confidence was placed risk (secondary prevention, diabetes mellitus, LDL-C 190 in the results of randomized, controlled trials but was inclu- mg/dL) if they are intolerant of the recommended dose of sive of all study designs. statin or have an inadequate response to statins. Although spe- cific LDL-C targets were not endorsed, the 2013 ACC/AHA Risk Assessment Model guideline recommended monitoring of the plasma lipid levels Similar to the 2013 ACC/AHA guideline, the 2011 ESC/EAS to ensure adherence, therapeutic response, and safety. guidelines supported the routine use of global cardiovascu- In comparison, the ATP III guidelines recommended a lar risk assessment for all adults without established CVD but treat-to-target strategy with specific LDL-C goals for each endorsed the use of the Systemic Coronary Risk Evaluation risk group. For primary prevention, the LDL-C goal was set (SCORE) risk assessment tool. The SCORE tool, derived at <100 mg/dL for high-risk individuals (10-year CHD risk by pooling data from cohort studies with participants in 12 >20%), <130 mg/dL for those at intermediate risk (10-year European countries, is designed to estimate the 10-year risk risk CHD risk, 10%20%), and <160 mg/dL for low-risk of fatal CVD event.19 The decision to include only fatal out- individuals (10-year CHD risk <10%). The LDL-C goal for come events was based on the assessment that fatal events are secondary prevention or primary prevention of CVD in those more easily calibrated in different populations and are less with diabetes mellitus was <100 mg/dL, with the option to likely than nonfatal events to be affected by local geographic target <70 mg/dL for those at highest risk of CVD.12,13 variations in diagnosis and treatment.19 The total CVD event In summary, the most important differences between the rate (including nonfatal events) has been shown to be 3-fold 2013 ACC/AHA guideline and the ATP III guidelines are the higher than the fatal CVD event rate.16 Variables included in introduction of the Pooled Cohort equations, the elimination the SCORE risk model include age, sex, systolic blood pres- of LDL-C treatment targets, and the lowering of the threshold sure, total cholesterol, and smoking status, and separate mod- at which statins should be considered to an estimated 10-year els are used for low- and high-risk European countries. absolute risk of 7.5%. The differences between these 2 docu- ments are summarized in Table1. To provide further context Treatment Recommendations for the 2013 ACC/AHA guideline, we next compare its rec- According to the 2011 ESC/EAS guidelines, patients are ommendations with those from other leading international considered to be very high risk for documented CVD, type 2 guidelines, as outlined in Table2. diabetes mellitus, type 1 diabetes mellitus with target organ damage, moderate to severe chronic kidney disease (CKD), or Clinical Vignette estimated 10-year absolute risk of fatal CVD 10%. High-risk With the Pooled Cohort equations, the patient in our clinical individuals are those with a 10-year risk of fatal CVD of 5% vignette would have an estimated 10-year absolute ASCVD to 9.9% or marked elevations in risk factors such as familial risk of 10.3%, and moderate- to high-intensity statin ther- dyslipidemia or severe hypertension. Moderate risk is defined apy could be considered after a clinician-patient discussion as a 10-year risk of fatal CVD of 1% to 4.9%, and low risk is of potential risk reduction, adverse effects, drug-drug inter- defined as an estimated 10-year risk of fatal CVD event <1%. actions, and patient preferences. With the modified FRS Extrapolating from clinical trials, the task force recommended endorsed by the ATP III guidelines, on the other hand, he LDL-C goals of approximately <70 mg/dL (1.8 mmol/L) for 1798CirculationMay 3, 2016

very high risk, <100 mg/dL (2.5 mmol/L) for high risk, <115 2014 National Institute for Health mg/dL (3.0 mmol/L) for moderate risk, and <190 mg/dL (4.9 and Care Excellence Guidelines mmol/L) for low risk. Therefore, the 2011 ESC/EAS guide- lines differ from the 2013 ACC/AHA guideline in the choice Methodology of risk assessment model, the estimated 10-year risk consid- The guidelines for lipid modification from the National ered sufficient to warrant medical treatment, and the contin- Institute for Health and Care Excellence (NICE) in England ued endorsement of specific LDL-C targets to guide therapy. were last updated in 2014.17 The NICE guidelines are similar in scope to the 2013 ACC/AHA guideline, with recommenda- Clinical Vignette tions for the primary and secondary prevention of CVD. Of According to the SCORE risk assessment tool, our patient the international guidelines reviewed, the NICE guidelines are has a 10-year estimated risk of CVD mortality of 5% if he noteworthy for the specificity of the drug recommendations lives in a high-risk European country and would be consid- provided and for the extent to which cost-effectiveness analy- ered at high risk. If he lives in a low-risk country, however, ses are used to justify the recommendations. his 10-year estimated risk of CVD death would be 3%, and he therefore would be considered at moderate risk. Regardless Risk Assessment Model of his country of residence, statin treatment would be recom- The NICE guidelines support the use of the QRISK2 risk mended, given the LDL-C targets of <100 mg/dL for high-risk assessment tool for global cardiovascular risk assessment in and <115 mg/dL for moderate-risk individuals. all adults <84 years of age who are free of CVD. The QRISK2 Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1799

Table 2. Comparison of International Guidelines for the Treatment of Blood Cholesterol

model estimates the 10-year absolute risk of CHD (angina or also recommended for those with diabetes mellitus and for myocardial infarction), stroke, or transient ischemic attack; is secondary prevention, with a goal of <70 mg/dL (1.8 mmol/L) specifically calibrated to the British population; and is updated considered to be optional for those at highest risk. annually. Compared with the Pooled Cohort equations and SCORE risk assessment tool, the QRISK2 multivariable model Clinical Vignette includes additional risk factors such as ethnicity, family his- The patient in our clinical vignette has an estimated 10-year tory of premature CHD, socioeconomic deprivation, body mass risk of total CVD of 16.6% according to the FRS and would index, rheumatoid arthritis, CKD, and atrial fibrillation (in addi- be characterized as intermediate risk. The LDL-C target for tion to age, sex, systolic blood pressure, total cholesterol, HDL- the intermediate-risk group is <130 mg/dL. Therefore, he C, hypertension treatment status, diabetes mellitus, and smoking would not be recommended to receive statin therapy. status, which are included in the Pooled Cohort equations).20 Comparison of International Guidelines Treatment Recommendations The 2013 ACC/AHA guideline differs substantially from its Similar to the 2013 ACC/AHA guideline, the 2014 NICE previous version, the ATP III guidelines, and other leading guidelines do not endorse a treat-to-target strategy. Instead, international guidelines. The effects of these changes were statin therapy is recommended for primary prevention in indi- illustrated by our representative clinical vignette, in which the viduals with type 2 diabetes mellitus or those without diabetes recommendations for initiating statin therapy for a 60-year-old mellitus but with an estimated 10-year absolute CVD risk of man with modest cardiometabolic risk factors varied accord-Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

10%. Statin therapy is also recommended for patients with ing to the guideline followed (Figure). The leading interna- type 1 diabetes mellitus who are >40 years of age with a dis- tional guidelines included in this review differ in 3 key areas: ease duration of >10 years or with evidence of target organ the suggested risk assessment model (component risk factors damage. Atorvastatin 20 mg daily is recommended for pri- and outcome evaluated), the threshold of risk considered suf- mary prevention, and atorvastatin 80 mg daily is used for sec- ficient to warrant initiating medical therapy, and the decision ondary prevention. In patients with CKD, 20 mg atorvastatin of whether to use a treat-to-target strategy. is suggested for both primary and secondary prevention. Predicted Impact of Changes Proposed Clinical Vignette The patient in our clinical vignette has an estimated 10-year by the 2013 ACC/AHA Guideline Dyslipidemia and cardiometabolic risk factors are highly CVD risk of 10.4% with the QRISK2 model and would thus prevalent in the population; therefore, changes to cholesterol meet the criteria for statin therapy as primary prevention. treatment guidelines will affect the treatment recommenda- tions for many people. Using data from the National Health 2012 Canadian Cardiovascular and Nutrition Examination Surveys (NHANES), Pencina and Society Guidelines colleagues demonstrated that 13 million American adults Methodology and Risk Assessment Model would be newly eligible for statin therapy with full imple- The Canadian Cardiovascular Society (CCS) guidelines for mentation of the 2013 ACC/AHA guideline.23 The increase in the diagnosis and treatment of dyslipidemia for the prevention statin eligibility was attributable primarily to a higher propor- of CVD in adults were last updated in 2012 (2012 CCS guide- tion of individuals 60 to 75 years of age meeting criteria for lines).18 The 2012 CCS guidelines recommend using the FRS treatment, which grew from 47.8% with the ATP III guidelines for total CVD events to estimate the 10-year absolute risk. to 77.3% with the 2013 ACC/AHA guideline. The true impact These guidelines also suggest doubling the estimated absolute of the 2013 ACC/AHA guideline is likely to be overestimated risk for individuals with a family history of premature CVD by these calculations, which assumed that all individuals in a on the basis of evidence of a 2-fold increase in CVD risk for statin benefit group would be treated with statins and there- FHS participants with a family history of premature CVD.21 fore did not consider the effect of a clinician-patient discus- The authors of the 2012 CCS guidelines advise considering sion (emphasized by the new guidelines specifically) of the cardiovascular age in addition to estimated 10-year absolute risks and benefits of statin initiation. Nevertheless, the 2013 risk when discussing lipid-lowering treatment with patients. ACC/AHA guideline is predicted to result in a higher number Cardiovascular age and heart age may be easier concepts of statin-eligible individuals in the United States. for patients to understand and may thereby facilitate shared The overall impact of a larger proportion of the popula- decision making between patient and provider.22 tion receiving statin therapy is uncertain. Although overtreat- ment is a concern,24 several recent studies have suggested Treatment Recommendations that the 2013 ACC/AHA guideline aligns more closely than The 2012 CCS guidelines endorse a treat-to-target strategy the ATP III guidelines with coronary atherosclerotic burden, with primary prevention LDL-C targets of <75 mg/dL (2.0 as assessed by coronary artery calcium score and computed mmol/L) for high-risk patients (10-year absolute risk 20%, tomography angiography.25,26 The features primarily responsi- CKD, or high-risk hypertension), <130 mg/dL (3.5 mmol/L) ble for the differences in statin allocation when the 2013 ACC/ for intermediate-risk individuals (10-year absolute risk, 10% AHA guideline is compared with the ATP III guidelines are 19%), and <190 mg/dL (5 mmol/L) for those at low risk (10- the risk assessment models used and the potential increase in year absolute risk <10%). A target LDL-C of <75 mg/dL is statin assignment to lower-risk primary prevention. Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1801

Absolute Risk Estimation: A well the model distinguishes those who develop the disease Comparative Critique from those who do not.36 With data from the Rotterdam Study, The Pooled Cohort equations were introduced alongside the investigators compared the performance of the Pooled Cohort 2013 ACC/AHA guideline with the goals of broadening eth- equations, the modified FRS, and the SCORE risk assess- nic and geographic diversity and incorporating stroke as an ment tool and determined that calibration was similarly poor outcome in the risk prediction model.14 Since their publica- among the 3 models, all of which significantly overestimated tion, several features of the Pooled Cohort equations have the risk of first CVD event.24 Furthermore, discrimination was been criticized, including potential overestimation of absolute modest (highest with the SCORE tool) among the 3 models risk, dependence on chronological age, and derivation in older (c statistics ranging from 0.670.77).24 Similarly, investigators cohorts with reduced performance in more contemporary from the MESA cohort evaluated the performance of 3 dif- cohorts. ferent FRSs, the Reynolds Risk Score, and the Pooled Cohort equations.31 They found modest calibration for the 5 scores, Absolute Risk Estimation with superior discrimination when the Reynolds Risk Score Overestimation of risk was first reported in the 2013 ACC/ was used. Despite the differences demonstrated in the above AHA guideline on the assessment of cardiovascular risk, dur- studies, there is little consensus on the optimal risk prediction model. ing external validation with data from the more contemporary Multi-Ethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) Choice of Variables and Optimizing ModelsDownloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

The different risk prediction models endorsed by the inter-

cohorts, and with updated data from ARIC and FHS.14 Several national cholesterol guidelines vary little in terms of the risk explanations for these findings were proposed. Foremost, a factors included as predictors, with the QRISK2 model being follow-up of at least 12 years was required for the derivation noteworthy for incorporating additional variables. Future cohorts to accurately predict 10-year risk. Therefore, secular consideration could be given to assessing the desirability, trends in statin use, revascularization procedures, or treat- appropriateness, and feasibility of establishing a more uni- ment of other risk factors such as hypertension and diabetes fied framework for estimating cardiovascular risk globally, mellitus may account for the lower rates of CVD observed in perhaps by developing an international CVD risk prediction more contemporary cohorts.2729 Underascertainment of clini- model. When data from international cohorts are combined, cally relevant events in the validation cohorts may also explain geographic, racial, and ethnic diversity can be optimized. The the apparent overestimation. In fact, when investigators used feasibility of this approach and the ability to calibrate a risk Medicare claims data to improve outcome ascertainment for score to different countries were recently demonstrated.37 Of the REGARDS study, they demonstrated improved perfor- course, there are several important hurdles to pursuing this mance of the Pooled Cohort equations.28 However, concerns approach globally. Primary among these is the lack of data about the Pooled Cohort equations remain. Overestimation has for certain geographic and ethnic groups. For example, the repeatedly been demonstrated in several modern cohorts,24,30,31 so-called BRIC countries of Brazil, Russia, India, and China and in at least the Womens Health Study, the overestimation represent 40% of the worlds population, but data on car- was not explained by differences in statin use, revascular- diovascular risk assessment in these countries are limited.38 izations, or underascertainment.27 Despite these findings, it Furthermore, the degree to which individual risk assessment is should be noted that the Womens Health Study was a primary affected by local characteristics that are not easily evaluated or prevention trial composed of clinical trial volunteers.32 The integrated into risk prediction models is uncertain. These may lower risk observed in this study might therefore be partially include factors such as local environment, diet, climate, air attributable to a healthy volunteer effect.33 pollution, built environment, cultural factors, availability of Although further investigation into the performance of health care, and genetic background. With the representative the Pooled Cohort equations may be warranted, it is worth patient in our clinical vignette, we observed important differ- considering whether other existing risk prediction models ences in the estimated risk using each of the 5 risk assess- perform better. This question is underscored by the observa- ment models. Although these differences could be partially tion that each of the leading international guidelines endorses explained by specific model characteristics, the unique local a different risk assessment model. Unfortunately, systematic factors may further contribute to variations in the weighting of comparisons between risk prediction models are rare, and variables, which could complicate direct comparison or har- results are often conflicting, depending on the characteristics monization of the different risk assessment models. of the populations studied.34 The FRS, for example, has been The 3 most important features of a risk prediction model shown to both overestimate and underestimate risk in different are the covariates included, the outcomes modeled, and the populations.35 time horizon. Optimization of each of these features may help further refine risk prediction techniques. As previously men- Model Performance Characteristics tioned, most existing risk prediction models rely primarily on Model calibration and discrimination are 2 features that can age, sex, cholesterol, blood pressure, hypertensive treatment be used to assess the performance of risk prediction models. status, diabetes mellitus, and smoking status. These individual Calibration, estimated by the Hosmer-Lemeshow statistic, rep- measurements do not account for variations in lifetime expo- resents how well the predicted risk approximates the observed sure to risk factors. Because traditional cardiovascular risk risk. Discrimination, measured by the c statistic, refers to how factors generally lead to atherosclerosis over decades, it is 1802CirculationMay 3, 2016

reasonable to hypothesize that the duration of exposure may that are independent of chronological age such as estimating be important. This approach is commonly used for cigarette cardiovascular age or lifetime risk are appealing alternatives smoking, which is recorded in pack-years of exposure, and because the primary prevention of ASCVD during the life there is evidence to support a similar approach with hyperten- course, as opposed to during 10-year windows, is the ultimate sion and dyslipidemia.3941 It is also notable that family history aim. Reflecting this concept, the Pooled Cohort equations pro- of premature CHD is included in the QRISK2 model and the vide an estimated lifetime risk for individuals 20 to 59 years modification of the FRS endorsed by the CCS but is not incor- of age, and the 2012 CCS guidelines endorse the use of heart porated into the SCORE or Pooled Cohort equations models. age in clinical decision making. However, further research is Because, as cited by the 2012 CCS guidelines, there are data required to determine how best to apply these assessments in supporting a 2-fold increased risk in those with a family his- routine care and to develop an evidentiary basis for interven- tory of premature CVD,21 it is intriguing that this variable did tions driven by such estimates. not meet the criteria for inclusion in certain models. Perhaps, it is related to how family history is defined or measured in Thresholds for Initiating Statin Therapy the derivation cohorts. Although not included as a covariable Whether a result of improved accuracy or of an overestimation in the Pooled Cohort equations model, the 2013 ACC/AHA of absolute risk, the Pooled Cohort equations partially explain guideline included family history of premature CVD as an the increase in statin-eligible adults with the 2013 ACC/AHA important factor that can be considered when a risk decision is guideline. However, the decision to lower the threshold at uncertain. In addition to improving how established risk fac- which primary prevention statin treatment should be consid-Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

tors are measured, discovery of new risk predictors (eg, using ered to an estimated 10-year absolute risk of ASCVD 7.5% genomic data, biomarkers, and advanced imaging techniques) is another crucial factor. In fact, this is the lowest threshold is an area of active investigation. used by the international guidelines reviewed here. High- The optimal outcomes to include in a CVD risk prediction risk status was defined as an estimated 10-year risk of CHD model remain uncertain. In particular, the inclusion of stroke >20% by the ATP III guidelines, fatal CVD 5% (equivalent in the Pooled Cohort equations has been questioned. Although to 15% for nonfatal events) by the 2011 ESC/EAS guide- CHD and myocardial infarction are almost exclusively caused lines, CVD 10% by the 2014 NICE guidelines, and 20% by atherosclerotic disease, stroke is a heterogeneous disorder by the 2012 CCS guidelines. It should be noted that because in which large-vessel atherosclerosis accounts for 40% of the outcomes included in the QRISK2 risk assessment tool the disease burden.4244 Because blood cholesterol is directly endorsed by the NICE guidelines include softer diagnoses related only to large-vessel atherosclerosis, using the same such as angina and transient ischemic attack, the 10% esti- risk factors to predict CHD and stroke may be overly sim- mated risk by this calculation is likely to be qualitatively plistic. In fact, low LDL-C has paradoxically been associated similar to the 7.5% absolute risk threshold of hard stroke and with a higher risk of hemorrhagic stroke in some studies.45 myocardial infarction events used by the 2013 ACC/AHA Furthermore, it is well described that the incidence of stroke in guideline. Furthermore, the decision to lower the threshold to the United States varies widely by geographic region, giving 7.5% is supported by recent evidence demonstrating both the rise to the term stroke belt to refer to a grouping of 11 south- benefits of statin therapy in primary prevention trials includ- eastern US states with age-adjusted stroke mortality rates that ing those with relatively low risk and very small adverse event are 10% higher than the national average.46 This area is not rates in meta-analyses of statin trials including 170000 par- well represented in the 4 National Heart, Lung, and Blood ticipants.49 In a meta-analyses by the Cholesterol Treatment Institute cohort studies used for the derivation of the Pooled Trialists Collaboration, statin treatment in people with a low Cohort equations. Therefore, using these equations to estimate risk (<10%) of CVD resulted in an absolute reduction in major the risk of stroke in the stroke belt will undoubtedly result in CVD events of 11 per 1000 over 5 years for each 39-mg/dL underestimation. Lastly, stroke disproportionally affects the reduction in LDL-C, which greatly exceeded any observed elderly, with 17% of all stroke patients >85 years of age, an hazard of statin therapy.50 A Cochrane review of statin efficacy age group that is underrepresented in the discovery cohorts.47 in primary prevention similarly found that the number needed Therefore, including stroke as an outcome might reduce model to treat to prevent an adverse CVD event was 167 for those precision and could further contribute to increased weighting with an estimated 5-year risk of <5% and 67 for those with of age in the risk prediction model. a 5-year risk of 5% to 10%.51 Moreover, using microsimula- tion modeling, Pandya and colleagues52 recently demonstrated Impact of Age on Absolute Risk Assessment that the 7.5% threshold is cost-effective, with an incremental Indeed, the dramatic effect of age on estimated risk is an addi- cost-effectiveness ratio of $37000 per quality-adjusted life- tional criticism of the Pooled Cohort equations, yet such age year gained. effects are observed to some extent in all of the previously In addition to increasing the number of statin-eligible mentioned risk prediction models. With the Pooled Cohort adults in the United States, another important consequence of equations, many older adults may exceed the 7.5% estimated the lowering of the treatment threshold is a reduction in the 10-year ASCVD risk threshold even in the absence of smok- proportion of individuals considered to be at intermediate risk, ing, diabetes mellitus, hypertension, or dyslipidemia.48 This which would decrease from 32% to 12% with full imple- feature is partially a result of the commonly used 10-year time mentation of the ACC/AHA guideline.53 The most appropriate window for risk prediction. The absolute event rate increases treatment for individuals at intermediate risk is, by definition, with age, as will the predicted risk. Therefore, approaches less certain; therefore, clinical judgment and additional testing Nayor and Vasan Comparison of Cholesterol Treatment Guidelines 1803

have historically been promoted for defining the treatment rec- the continued use of cholesterol targets includes a number of ommendations in this group. Significant attention has focused primary and secondary prevention statin trials demonstrat- on developing and validating blood and imaging biomarkers ing improved outcomes with more intensive LDL-C lower- to improve the precision of risk estimates for these individu- ing.49,50,5962 However, none of these trials used specific LDL-C als. By lowering the treatment threshold, the 2013 ACC/AHA targets to trigger medication dose adjustments, so LDL-C guideline is proposing that the recent evidence, reviewed targets are extrapolated from these trials. This is a highly above, supports the use of statin therapy in most adults who controversial area in which randomized, controlled trial data were previously in the intermediate-risk category and there- and everyday clinical practice appear to conflict. Innovative fore that the group of individuals in whom there is equipoise investigative techniques are needed to evaluate the effects concerning the most appropriate treatment has diminished. of treat-to-target strategies on patient outcomes, incorporat- The international guidelines that we have reviewed endorse ing the short-term effects of lipid lowering and the long-term basing treatment decisions on estimated absolute CVD risk. effects related to patient well-being and encouraging healthy However, recent publications have suggested potential modifi- lifestyle behaviors. cations to these methods. Navar-Boggan and colleagues54 have Two developments since the publication of the 2013 ACC/ recently demonstrated the potential benefit of using age- and AHA guideline may further complicate the target-agnostic sex-specific 10-year risk thresholds to guide therapy, includ- approach. First is the publication of the results from the Improved ing raising the treatment threshold for adults 66 to 75 years of Reduction of Outcomes: Vytorin Efficacy International Trial age to 10% in women and 15% in men. Alternatively, Ridker (IMPROVE-IT), which demonstrated a 2% absolute risk reduc-Downloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

and colleagues55 have proposed a hybrid algorithm that would tion of CVD events with ezetimibe added to statin therapy in incorporate clinical trial data into the primary prevention algo- patients after myocardial infarction.10 Individuals receiving rithm, although the superiority of this strategy is uncertain.56 the combination of simvastatin and ezetimibe had lower aver- These strategies warrant additional investigation to determine age LDL-C levels (53.2 versus 69.9 mg/dL), suggesting that whether they might be used to improve future cholesterol lower is better for LDL-C cholesterol, at least in the context guidelines. of secondary prevention. The second development is the recent approval by the US Food and Drug Administration of 2 drugs Treatment Targets for from the new class of proprotein-convertase subtilisin/kexin Lipid-Lowering Treatment type 9 inhibitors. While studies assessing the impact on hard Another important modification introduced by the 2013 CVD outcomes are ongoing, these drugs appear to be safe and ACC/AHA guideline was the removal of specific treatment effective in lowering LDL.63 The IMPROVE-IT trial was the targets for lipid-lowering therapy. In explaining its rationale, first to demonstrate the benefit of adding a nonstatin medication the guideline committee referred to the absence of clinical in patients already treated with statins for secondary preven- trial data indicating what the precise targets should be, the tion. As the options for nonstatin LDL-Clowering medications lack of proven benefit for 1 target versus another, the inability proliferate, future guideline committees will be tasked with to account for adverse effects of striving to achieve a given evaluating whether a return to LDL-C treatment targets (at least goal, and concern that target-based strategies may result in certain circumstances) might be warranted to guide the addi- in undertreatment with statins or overtreatment with non- tion of these new pharmacological options in certain high-risk statins to reach these goals.11 Additionally, there are small patients already treated with statins.64 but significant differences between estimating LDL-C con- centrations with the Friedewald formula and direct measure- Primary Prevention Approaches for ments.57 Thus, with a treat-to-target strategy, the same patient Those With Diabetes Mellitus or CKD might have different recommendations depending on the Despite variations in the language used and details about the LDL-C assay used. On the other hand, critics of this tar- suggested statin dose, the international guidelines generally get-agnostic approach have argued that treatment goals are agree on the approach to primary prevention in those with dia- valuable in clinical practice in that they serve to reinforce betes mellitus (Table2 provides details). The notable differ- patients positive behaviors and lifestyle changes and provide ences pertain mostly to the treatment of patients <40 years of patients and their providers with tangible goals and metrics.58 age, in whom there is scant evidence on the appropriateness of Furthermore, removing treatment targets makes it difficult for statin treatment for the primary prevention of CVD. patients to improve their risk profiles (by nonpharmacologi- Agreement among the guidelines is less uniform for the cal means) sufficiently to no longer warrant pharmacother- treatment of individuals with CKD. The 2013 ACC/AHA apy. Starting a preventive medication without the possibility guideline is alone among the international guidelines reviewed of discontinuing the medication in the future may be a philo- in not considering the presence of CKD to confer high risk. sophical challenge from a public health perspective because it The 2011 ESC/EAS and 2012 CCS guidelines characterize essentially medicalizes a large proportion of the community patients with CKD as high to very high risk and recommend while de-emphasizing the potential importance of lifestyle statin treatment to achieve the appropriate LDL-C targets.16,18 modifications. The 2014 NICE guidelines recommend starting atorvastatin Although the most recent NICE guidelines similarly do 20 mg for all patients with CKD.17 The 2013 ACC/AHA, 2011 away with treatment targets, the latest ESC/EAS and CCS ESC/EAS, 2014 NICE, and 2012 CSS documents all agree guidelines continue to endorse treat-to-target strategies.16,18 that there is insufficient evidence to support specific recom- In the ESC/EAS and CCS guidelines, the justification for mendations for patients with end-stage renal disease receiving 1804CirculationMay 3, 2016

regular hemodialysis. Although the 2013 ACC/AHA guide- settings (beginning with a clinician-patient discussion) to a line is unique among the international guidelines reviewed 10-year absolute ASCVD risk of 7.5%, and removing choles- in not treating all individuals with CKD as high risk, using terol treatment targets. After reviewing several leading inter- data from the REGARDS study, Colantonio and colleagues65 national guidelines, we observe a lack of consensus on the demonstrated that only 8% of individuals with CKD who are optimal approach to risk assessment, treatment thresholds, 50 to 79 years of age would not qualify for consideration of or the use of cholesterol targets among these guidelines. As a statin therapy on the basis of the 2013 ACC/AHA guideline. result, the recommendations for primary prevention lipid-low- Therefore, whether this distinction between the 2013 ACC/ ering therapy for an individual vary according to which guide- AHA and other guidelines actually affects individual-level line is followed, as illustrated by the clinical vignette. These recommendations is uncertain. observations underscore the importance of further investiga- tion aimed at refining risk prediction models and determining Other Recent US Guidelines the optimal strategies for monitoring and adjusting medical Since the publication of the 2013 ACC/AHA guideline, the therapy. US Preventive Services Task Force (USPSTF)48 and National Lipid Association (NLA)66 have released recommendations Sources of Funding for CVD prevention. Agreement between the recommenda- Dr Nayor was supported by training grant T32-HL007604 from the tions from the USPSTF draft statement (which focuses on National Institutes of Health and by the Clinical Skills Development Core Training National Heart, Lung, and Blood Institute primary prevention) and the 2013 ACC/AHA guideline isDownloaded from http://circ.ahajournals.org/ by guest on November 5, 2017

Yates GM, Stone JA, Ur E. 2012 Update of the Canadian Cardiovascular cular risk. Curr Opin Lipidol. 2006;17:375386. doi: 10.1097/01. Society guidelines for the diagnosis and treatment of dyslipidemia for mol.0000236362.56216.44. the prevention of cardiovascular disease in the adult. Can J Cardiol. 36. Cook NR. Use and misuse of the receiver operating characteristic

Data Supplement (unedited) at:

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Circulation is online at: